WO2011154708A1 - Dérivés de benzamide et leur utilisation comme inhibiteurs de hsp90 - Google Patents

Dérivés de benzamide et leur utilisation comme inhibiteurs de hsp90 Download PDF

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Publication number
WO2011154708A1
WO2011154708A1 PCT/GB2011/000879 GB2011000879W WO2011154708A1 WO 2011154708 A1 WO2011154708 A1 WO 2011154708A1 GB 2011000879 W GB2011000879 W GB 2011000879W WO 2011154708 A1 WO2011154708 A1 WO 2011154708A1
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Prior art keywords
phenyl
dihydroxy
propan
carbonyl
piperidin
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PCT/GB2011/000879
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English (en)
Inventor
Alastair David Graham Donald
Joanne Mcdermott
Sanjay Ratilal Patel
David Festus Charles Moffat
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Chroma Therapeutics Ltd
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Publication date
Priority to CN201180038937.2A priority Critical patent/CN103068799B/zh
Priority to MX2012014506A priority patent/MX341341B/es
Application filed by Chroma Therapeutics Ltd filed Critical Chroma Therapeutics Ltd
Priority to SG2012090304A priority patent/SG186232A1/en
Priority to CA2802279A priority patent/CA2802279A1/fr
Priority to ES11726470.5T priority patent/ES2587256T3/es
Priority to DK11726470.5T priority patent/DK2580193T3/en
Priority to JP2013513747A priority patent/JP5955317B2/ja
Priority to NZ605558A priority patent/NZ605558A/en
Priority to KR1020137000721A priority patent/KR20130112026A/ko
Priority to US13/703,387 priority patent/US9321718B2/en
Priority to EP11726470.5A priority patent/EP2580193B1/fr
Priority to EA201270816A priority patent/EA021237B1/ru
Priority to BR112012031634A priority patent/BR112012031634A2/pt
Priority to AU2011263543A priority patent/AU2011263543B2/en
Publication of WO2011154708A1 publication Critical patent/WO2011154708A1/fr
Priority to IL223514A priority patent/IL223514A/en
Priority to ZA2013/00036A priority patent/ZA201300036B/en
Priority to US15/073,352 priority patent/US20160193200A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • This invention relates to a series of amino acid derivatives, to compositions containing them, to processes for their preparation and to their use in medicine as HSP90 inhibitors.
  • the compounds may also be of use in the treatment of cell proliferative diseases such as cancer which are mediated by aberrant HSP90 activity as well as inflammatory and immune disorders such as rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), psoriasis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, and disorders related to angiogenesis such as age related macular degeneration, diabetic retinopathy and endometriosis.
  • the compounds may also be of use in the protection of normal cells against the action of cytotoxic agents.
  • Hsps Heat shock proteins
  • Hsps are molecular chaperones that assist general protein folding and prevent non-functional side reactions such as non-specific aggregation of misfolded or unfolded proteins, even under normal conditions. They account for 1 to 2% of total protein in unstressed cells. However, their levels of intracellular expression increase in response to protein- denaturing stressors, such as temperature change, as an evolutionarily conserved response to restore the normal protein-folding environment and to enhance cell survival.
  • the essential chaperoning functions of Hsps are subverted during oncogenesis to make malignant transformation possible and to facilitate rapid somatic evolution.
  • Hsp90 heat shock protein 90kDa
  • Hsp90 heat shock protein 90kDa
  • client proteins target or “client” proteins, among them many steroid hormone receptors, protein kinases and transcription factors. It interacts with client-proteins by facilitating their stabilisation and activation or by directing them for proteasomal degradation. Thanks to its multifaceted ability to influence signal transduction, chromatin remodelling and epigenetic regulation, development and morphological evolution, it is considered as a promising target for cancer therapy.
  • the Hsp90 protein contains three well-defined domains, each of these plays a crucial role in the function of the protein.
  • the N-terminal domain, binding site for ATP is also the binding site for Geldanamycin, a representative of the ansamycin drugs that specifically target Hsp90.
  • the middle domain completes the ATPase site and binds to client proteins.
  • Hsp90 forms homo-dimers where the contact sites between subunits are localised within the C- terminus in the open conformation of the dimer.
  • the three domains of Hsp90 move from an ATP-free "open" state to an ATP-bound "closed” state.
  • Hsp90 The functions of Hsp90 include assisting in protein folding, cell signaling, and tumor repression. In unstressed cells, Hsp90 plays a number of important roles, which include assisting in folding, intracellular transport, maintenance, and degradation of proteins as well as facilitating cell signaling.
  • Hsp90 inhibitors such as the natural products belonging to the ansamycins or radicicol families or synthetic purines, bind at the ATP-site on the N-terminal domain, resulting in client protein deactivation, destabilisation and degradation.
  • compounds such as novobiocin and cisplatin have been reported to bind to the C-terminal domain of Hsp90, resulting in an anti -cancer effect as well.
  • Inhibition of Hsp90 can also be a result of inactivation through post-translational modification, typically acetylation or ubiquitinylation. When Hsp90 is inhibited, its regulatory functions are disrupted.
  • Hsp90 As Hsp90 is involved in the regulation of many relevant oncoproteins, it is suggested that its inhibition will result in a broad range of biological activities, hence the Hsp chaperone molecule is an appealing target for cancer. Cancerous cells over-express a number of proteins, including PI3K and AKT and inhibition of these two proteins triggers apoptosis. As Hsp90 stabilizes the PI3K and AKT proteins, its inhibition appears to induce apoptosis through inhibition of the PI3K/AKT signaling pathway. Together with its co-chaperones, Hsp90 modulates tumour cell apoptosis, mediated through effects on AKT, tumor necrosis factor receptors (TNFR) and nuclear factor- ⁇ (NF- ⁇ ) function. Finally Hsp90 participates in many key processes in oncogenesis such as self-sufficiency in growth signals, stabilization of mutant proteins, angiogenesis, and metastasis.
  • TNFR tumor necrosis factor receptors
  • NF- ⁇ nuclear factor
  • Hsp90 also plays an important role in regulating pro-inflammatory signalling pathways. For example, agonists that stimulate NO production were reported to activate a mechanism that recruits Hsp90 to the eNOS. Interaction between Hsp90 and eNOS enhances activation of the enzyme in cells and in intact blood vessels leading to NO production.
  • Geldanamycin a known natural inhibitor of Hsp90, was shown to be anti-inflammatory in vivo.
  • Geldanamycin treatment was also shown to induce a significant reduction in IKK protein levels.
  • IKK phosphorylates ⁇ , marking it for subsequent proteasomal degradation. It is therefore a crucial regulator of the NF- ⁇ pathway, which holds prominent roles in inflammation and cancer. It has been shown that Hsp90 inhibitors prolong survival, reduce or abolish systemic and pulmonary inflammation, and restore normal lung function in a murine model of sepsis.
  • Sepsis is associated with activation of pro-inflammatory mediators, including NF- ⁇ , an important pro-inflammatory transcription factor that mediates up-regulated expression of several pro-inflammatory cytokines and chemokines, such as tumour necrosis factor a (TNF- a), IL-6, IL-8 and IL- ⁇ , critical for amplifying the inflammatory insult.
  • NF- ⁇ an important pro-inflammatory transcription factor that mediates up-regulated expression of several pro-inflammatory cytokines and chemokines, such as tumour necrosis factor a (TNF- a), IL-6, IL-8 and IL- ⁇ , critical for amplifying the inflammatory insult.
  • TNF- a tumour necrosis factor a
  • IL-6 IL-6
  • IL-8 IL-8
  • IL- ⁇ critical for amplifying the inflammatory insult.
  • Hsp90-complexing to the glucocorticoid receptor (GR) is necessary to maintain GR in a conformation able to bind hormone.
  • Hsp90 Binding of the hormone to GR causes a conformational change in the complex which results in the interaction between Hsp90 and GR to be disrupted: the receptor then translocates from the cytoplasm to the nucleus, dimerizes and binds to DNA to activate the transcription of the target genes.
  • Hsp90 is also required for the proper functioning of several other steroid receptors, including those responsible for the binding of aldosterone, androgen, estrogen and progesterone.
  • HSP90 has also been implicated in a number of other conditions, such as viral infection and Alzheimer' s Disease. " :
  • a group of compounds has now been identified which are potent and selective inhibitors of HSP90 and the isoforms and splice variants thereof.
  • the compounds are charactrised by the presence in the molecule of an amino acid motif or an amino acid ester motif which is hydrolysable by intracellular carboxylesterases.
  • Compounds of the invention having lipophilic amino acid ester motifs cross the cell membrane, and are hydrolysed to the acid by said carboxylesterases.
  • the polar hydrolysis product accumulates in the cell since it does not readily cross the cell membrane and hence the Hsp90 inhibitory activity of the compound is prolonged and enhanced.
  • the compounds of the invention are related to the HSP90 inhibitors encompassed by the disclosures in WO2006/109075, WO2006/109085 and WO2006/117669 but differ therefrom in that the present compounds have the amino acid motif referred to above.
  • the compounds are thus of use in medicine, for example in the treatment of a variety of proliferative disease states, where inappropriate action of HSP90 may be involved such as cancer, inflammatory and immune disorders such as rheumatoid arthritis, COPD, psoriasis, Crohn's disease, ulcerative colitis, systemic lupus erythmatosis, and disorders related to angiogenesis such as age related macular degeneration, diabetic retinopathy and endometriosis.
  • Inhibitors of Hsp90 may be useful in the treatment of inflammation. Inflammation is mediated by a variety of soluble factors, including a group of secreted polypeptides known as cytokines. Those which mediate acute inflammation include IL- 1, TNF-a, IL-6, IL-11, IL-8, G-CSF, and M-CSF.
  • Cytokines involved in chronic inflammation can be subdivided into cytokines mediating humoral responses such as IL- 4, IL-5, IL-6, IL-7, and IL-13, and those mediating cellular responses such as IL-1 L-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, interferons, transforming growth factor-b, and tumor necrosisfactor a and b.
  • Some cytokines, such as IL-1 significantly contribute to both acute and chronic inflammation.
  • the compounds may also be of use in the protection of normal cells against the action of cytotoxic agents or in the management of viral infection or Alzheimer's Disease.
  • the invention provides a compound which is (a) a phenylamide derivative of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate, prodrug or solvate thereof:
  • R L is hydrogen or hydroxy
  • R 2 , R 3 , R 4 and R 5 are the same or different and represent hydrogen or halogen atoms or Ci -6 alkyl, C 2-6 alkenyl, C 2 ⁇ alkynyl, C 1-6 alkoxy, hydroxy, cyano, nitro or -NR ' R " groups wherein R ' and R " are the same or different and represent hydrogen or unsubstituted Ci_ alkyl, and with the proviso that no more than two of R 2 , R 3 , R 4 and R 5 are cyano or nitro;
  • R 6 is selected from C alkyl and R 7 represents -CR 8 R 9 -A
  • R and R are the same or different and represent a hydrogen or halogen atom or a C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, hydroxy or -NR ' R " group where R ' and R " are the same or different and represent hydrogen or unsubstituted C alkyl, and A represents a phenyl ring or a 5- or 6-membered heteroaryl group and is substituted with a group W; or
  • R and R together with the nitrogen atom to which they are bonded, form a 5- or 6-membered heterocyclyl group which is either (a) unfused, or (b) fused to a phenyl ring or a 5- to 6- membered heteroaryl group, and wherein either the heterocyclyl group or, when fused, the heterocyclyl group or the phenyl ring or heteroaryl group to which it is fused, is substituted with a group W;
  • W represents a group -Alk'-R;
  • Alk 1 represents a bond, a C 1-4 alkylene group or a group -(CM alkylene)-NR ' -(C alkylene)- wherein R ' represents hydrogen or C alkyl;
  • R 10 represents a hydrogen atom or a C alkyl group
  • Alk 2 represents a group of formula -C(R 12 )(R 13 )- when R is of formula
  • R 12 and R 13 are the same or different and represent hydrogen or the a-substituents of an a- substituted or ⁇ , ⁇ -disubstituted glycine or glycine ester compound; ring D, where present, is a 5- to 6-membered heterocyclyl group
  • R 11 is a group -COOH or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a -COOH group;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , Alk 1 , R 12 and R 13 are unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms and C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, C 2-4 alkenyloxy, C haloalkyl, C 2 ⁇ haloalkenyl, C haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR ' , cyano, nitro, C 1-4 hydroxyalkyl and -NR ' R ' ' groups where R' and R ' ' are the same or different and represent hydrogen or unsubstituted C 1-2 alkyl; and
  • R 6 and R 7 are unsubstituted or substituted by 1 , 2, 3 or 4 unsubstituted substituents selected from halogen atoms, and cyano, nitro, C alkyl, C alkoxy, C 2- 4 alkenyl, C 2-4 alkenyloxy, C haloalkyl, C 2- 4
  • each R ' and R " is the same or different and represents hydrogen or unsubstituted C 1-4 alkyl, or from substiruents of formula -COOH, -COOR A , -COR A , -S0 2 R A , -CONH2, -SO2NH2, -CONHR A , -S0 2 NHR A , -CONR A R B , -S0 2 NR A R B , -OCONH 2 , -OCONHR A , -OCONR A R B , -NHCOR A , -NR B COR A , -NHCOOR A , -NR B COOR A , -NR B COOH, -NHCOOH, -NHS0 2 R A
  • R A and R B are the same or different and represent unsubstituted C 1- alkyl, C 3-6 cycloalkyl, non- fused phenyl or a non-fused 5- to 6-membered heteroaryl, or R A and R B when attached to the same nitrogen atom form a non-fused 5- or 6- membered heterocyclyl group.
  • R 12 and/or R 13 represent the a substiruents or an a-substituted or a,a- disubstituted glycine or glycine ester compound
  • any functional groups in these R and R groups may be protected.
  • the term "protected" when used in relation to a functional substituent in a side chain of an a-amino acid means a derivative of such a substituent which is substantially nonfunctional. Suitable protecting groups will be described later.
  • the compounds of the invention contain a motif which is hydrolysable by an intracellular carboxylesterase.
  • Compounds of the invention can cross the cell membrane, and, if in the ester form, can be hydrolysed to the acid by the intracellular carboxylesterases.
  • the polar hydrolysis product accumulates in the cell since it does not readily cross the cell membrane. Hence the HSP90 activity of the compound is prolonged and enhanced within the cell.
  • the compounds of the invention are phenylamide derivatives of formula (I) or tautomers thereof, or pharmaceutically acceptable salts thereof.
  • the invention provides the use of a compound as defined above in the manufacture of a medicament for inhibiting the activity of HSP90. More preferably, the invention provides the use of a compound as defined above in the manufacture of a medicament for use in treating a disorder mediated by HSP90.
  • the invention provides a compound as defined above for use in treating the human or animal body, or for use in inhibiting the activity of HSP90. More preferably, the invention provides the use of a compound as defined above for use in treating or preventing disorders mediated by HSP90.
  • the invention also provides a pharmaceutical composition which comprises a compound as defined above and a pharmaceutically acceptable carrier or diluent.
  • the compounds with which the invention is concerned may be used for the inhibition of HSP90 activity ex vivo or in vivo.
  • the compounds of the invention are also particularly useful in the treatment of inflammation, for example in the treatment of rheumatoid arthritis.
  • the compounds of the invention are also particularly useful in the treatment of cancer, in particular breast cancer, ovarian cancer, pancreatic cancer and hepatocellular carcinoma.
  • the compounds of the invention may be used in the preparation of a composition for treatment of cancer (for example monocyte-derived cancers), inflammatory and immune disorders such as rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, and disorders related to angiogenesis age related macular degeneration, diabetic retinopathy and
  • cancer for example monocyte-derived cancers
  • inflammatory and immune disorders such as rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, and disorders related to angiogenesis age related macular degeneration, diabetic retinopathy and
  • the compounds may also be of use in the protection of normal cells against the action of cytotoxic agents or in the management of viral infection or Alzheimer's Disease.
  • the compounds with which the invention is concerned are of use for inhibition of Hsp90 activity.
  • Inhibition of Hsp90 activity is a mechanism for treatment of a variety of diseases, including cell proliferative disease such as cancer (including malignancies of the monocytic cell lineage, e.g., juvenile myelomonocytic leukaemia) and psoriasis, polyglutamine disease such as Huntingdon's disease, neurogenerative disease such as Alzheimers disease, autoimmune disease such as rheumatoid arthritis (including systemic juvenile idiopathic arthritis), diabetes, haematological disease, inflammatory disease, cardiovascular disease, atherosclerosis, primary biliary cirrhosis, Wegener's granulomatosis, and the inflammatory sequelia of infection.
  • cancer including malignancies of the monocytic cell lineage, e.g., juvenile myelomonocytic leukaemia
  • psoriasis polyglutamine disease
  • diseases treatable by inhibition of HSP90 activity are cell proliferative disease such as cancer (including malignancies of the monocytic cell lineage, e.g., juvenile myelomonocytic leukaemia) and psoriasis, polyglutamine disease such as Huntingdon's disease, neurogenerative disease such as Alzheimers disease, autoimmune disease such as rheumatoid arthritis (including systemic juvenile idiopathic arthritis), haematological disease, inflammatory disease, cardiovascular disease, atherosclerosis, primary biliary cirrhosis, Wegener's granulomatosis, and the inflammatory sequelia of infection.
  • cancer including malignancies of the monocytic cell lineage, e.g., juvenile myelomonocytic leukaemia
  • psoriasis polyglutamine disease
  • polyglutamine disease such as Huntingdon's disease
  • neurogenerative disease such as Alzheimers disease
  • autoimmune disease such as rheumatoi
  • Autoimmune disease often has an inflammatory component.
  • Such conditions include acute disseminated alopecia universalise, ANCA positive diseases, Behcet's disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, inflammatory bowel disease, Crohn's disease, diabetes mellitus type 1, Fanconi syndrome, giant cell arteritis, glomerulonephritis, Goodpasture's syndrome, Grave's disease, Guillain-Barre syndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki's disease, systemic lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis,
  • inflammatory conditions which may be treated with the compounds of the invention include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, ulceris, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, percarditis, peritonoitis, pharyngitis, pleuritis; pneumonitis, prostatistis, pyelonephritis, and stomatisi, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts, and heart valve xengrafts, sewrum sickness, and graft vs host disease
  • Preferred treatments using compounds of the invention include treatment of transplant rejection, rheumatoid arthritis, psoriatic arthritis, Type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosis, and inflammation accompanying infectious conditions (e.g., sepsis), psoriasis, Crohns disease, ulcerative colitis, chronic obstructive pulmonary disease, multiple sclerosis, atopic dermatitis, and graft versus host disease.
  • infectious conditions e.g., sepsis
  • psoriasis psoriasis
  • Crohns disease Crohns disease
  • ulcerative colitis chronic obstructive pulmonary disease
  • multiple sclerosis atopic dermatitis
  • graft versus host disease graft versus host disease.
  • compounds of the invention may be used in the treatment of transplant rejection, rheumatoid arthritis, psoriatic arthritis, asthma, inflammatory bowel disease, systemic lupus erythematosis, and inflammation accompanying infectious conditions (e.g., sepsis), psoriasis, Crohns disease, ulcerative colitis, chronic obstructive pulmonary disease, multiple sclerosis, atopic dermatitis, and graft versus host disease.
  • infectious conditions e.g., sepsis
  • psoriasis Crohns disease
  • ulcerative colitis e.g., chronic obstructive pulmonary disease
  • multiple sclerosis e.g., multiple sclerosis
  • atopic dermatitis e.g., graft versus host disease.
  • Another preferred use of the compounds of the invention is in the treatment of cancers, in particular in the treatment of breast cancer, ovarian cancer, pancreatic cancer and hepatocellular carcinoma.
  • the compounds with which this invention is concerned should have molecular weights of no more than 900, more preferably no more than 600.
  • the alkyl, alkenyl and alkynyl groups and moieties in R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , Alk 1 , R 12 and R 13 are unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms and C alkyl, C 2- 4 alkenyl, CM alkoxy, C 2-4 alkenyloxy, C haloalkyl, C 2-4 haloalkenyl, C haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, -SR', cyano, nitro, C hydroxyalkyl and -NR
  • Preferred substituents include halogen atoms and C alkyl, C 2-4 alkenyl, CM alkoxy, C 2-4 alkenyloxy, CM haloalkyl, C 2- 4 haloalkenyl, CM haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, mercapto, cyano, nitro, CM hydroxyalkyl, C 2-4
  • substituents include halogen, C 1-4 alkyl, C 2- 4 alkenyl, C
  • substituents include unsubstituted C alkyl, CM alkoxy, hydroxyl and -NR'R" groups where R ' and R" are the same or different and represent hydrogen or unsubstituted Ci -2 alkyl.
  • alkyl, alkenyl and alkynyl moieties are substituted by two or three substituents, it is preferred that not more than two substituents are selected from cyano and nitro. More preferably, not more than one substituent is selected from cyano and nitro.
  • a Ci -6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, for example a C 1-4 alkyl group or moiety containing from 1 to 4 carbon atoms.
  • CM alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
  • the alkyl moieties may be the same or different.
  • a C 2-6 alkynyl group or moiety is a linear or branched alkynyl group or moiety containing from 2 to 6 carbon atoms, for example a C -4 alkynyl group or moiety containing from 2 to 4 carbon atoms.
  • Exemplary alkynyl groups include -C ⁇ CH or -CH 2 -C ⁇ CH, as well as 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
  • two alkynyl moieties may be the same or different.
  • a Ci -6 alkylene group or moiety is a linear or branched alkylene group or moiety, for example a C alkylene group or moiety. Examples include methylene, n-ethylene, n-propylene and -C(CH 3 ) 2 - groups and moieties.
  • a C 2-6 alkenylene group or moiety is a linear or branched alkenylene group or moiety, for example a C 2- 4 alkenylene group or moiety.
  • a C 2-6 alkynylene group or moiety is a linear or branched alkynylene group or moiety, for example a C 2-4 alkynylene group or moiety. Examples include -C ⁇ C-, -C ⁇ C-CH 2 - and -CH 2 -C ⁇ C-.
  • a halogen atom is typically chlorine, fluorine, bromine or iodine.
  • a C 1-6 alkoxy group or C 2- alkenyloxy group is typically a said
  • Ci-6 alkyl e.g. a C alkyl
  • a said C 2-6 alkenyl e.g. a C 2-4 alkenyl
  • a haloalkyl, haloalkenyl, haloalkoxy or haloalkenyloxy group is typically a said alkyl, alkenyl, alkoxy or alkenyloxy group respectively which is substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms.
  • Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX 3 and -OCX 3 wherein X is a said halogen atom, for example chlorine and fluorine.
  • a C hydroxyalkyl group is a C1-4 alkyl group substituted by one or more hydroxy groups. Typically, it is substituted by one, two or three hydroxy groups. Preferably, it is substituted by a single hydroxy group.
  • a 5- or 6- membered heteroaryl group or moiety is a
  • heteroatoms for example 1, 2, 3 or 4 heteroatoms, selected from O, S and N.
  • examples include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazolyl groups.
  • Thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl groups are preferred, e.g. pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl groups.
  • More preferred groups are thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl and triazinyl, e.g. pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl and triazinyl.
  • a 4- to 7-membered heterocyclyl group or moiety is a non- aromatic, saturated or unsaturated C 4-7 carbocyclic ring in which one or more, for example 1 , 2, 3 or 4, of the carbon atoms are replaced with a moiety selected from N, O, S, S(O) and S(0) 2 , and wherein one or more of the remaining carbon atoms is optionally replaced by a group -C(O)- or -C(S)-.
  • Preferred heterocyclyl groups are 5- and 6-membered heterocyclyl groups.
  • Suitable heterocyclyl groups and moieties include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, methylenedioxyphenyl, ethylenedioxyphenyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S,S-dioxo-thiomorpholinyl, morpholinyl, 1 ,2-dioxolanyl, 1
  • Preferred heterocyclyl groups are pyrrolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, thiomo holinyl and mo holinyl groups and moieties. More preferred heterocyclyl groups are pyrrolidinyl, imidazolidinyl, oxazolidinyl,
  • Particularly preferred groups include piperidinyl and pyrrolidinyl.
  • heterocyclyl group or moiety When a heterocyclyl group or moiety is fused to another group, it may be fused to a further phenyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl group. When a heterocyclyl group or moiety is fused to another group, it may be fused to a further phenyl or 5- to 6-membered heteroaryl group, more preferably to a phenyl group.
  • Preferred fused heterocyclyl groups include indolinyl, isoindolinyl, 2,3-dihydro- lH-benzo[d]imidazolyl, 2,3-dihydro-lH-indazolyl, 2,3-dihydrobenzo[d]thiazolyl, 2,3- dihydrobenzo[d]isothiazolyl and 2,3-dihydrobenzo[d]oxazole 2,3- dihydrobenzo[d]isoxazolyl. More preferred fused heterocyclyl groups include indolinyl and isoindolinyl, most preferably isoindolinyl.
  • heteroaryl and heterocyclyl groups refer to an "N" moiety which can be present in the ring, as will be evident to a skilled chemist the N atom will be protonated (or will carry a substituent as defined below) if it is attached to each of the adjacent ring atoms via a single bond.
  • a C 3-7 carbocyclic group or moiety is a non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 7 carbon atoms.
  • it is a saturated or mono-unsaturated hydrocarbon ring (i.e. a cycloalkyl moiety or a cycloalkenyl moiety) having from 3 to 7 carbon atoms, more preferably having from 3 to 6 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and their mono-unsaturated variants, more particularly cyclopentyl and cyclohexyl.
  • a C 3-7 carbocyclyl group or moiety also includes C 3-7 carbocyclyl groups or moieties described above but wherein one or more ring carbon atoms are replaced by a group -C(O)-. More preferably one or two ring carbon atoms (most preferably two) are replaced by -C(O)-.
  • a preferred such group is benzoquinone.
  • a carbocyclyl group or moiety When a carbocyclyl group or moiety is fused to another group, it may be fused to a further phenyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl ring. For example it may be fused to a further phenyl ring.
  • An exemplary fused carbocyclyl group is indanyl. More preferably carbocyclyl groups are monocyclic (i.e. non-fused).
  • the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties are unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents selected from halogen atoms, and cyano, nitro, C alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkenyloxy, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 1-4 haloalkoxy, C 2-4 haloalkenyloxy, hydroxyl, C 1-4 hydroxyalkyl, -SR' and -NR ' R" groups wherein each R' and R" is the same or different and represents hydrogen or unsubstituted C ⁇ alkyl, or from substituents of formula -COOH, -COOR A , -COR A , -S0 2 R A , -CONH 2 , -S0 2 NH 2 , -CONHR A
  • R A and R B are the same or different and represent unsubstituted Ci -6 alkyl, C 3-6 cycloalkyl, non-fused phenyl or a non-fused 5- to 6-membered heteroaryl, or R A and R B when attached to the same nitrogen atom form a non-fused 5- or 6-membered heterocyclyl group.
  • the substituents are preferably themselves unsubstituted. In particular it is preferred that R A and R B are unsubstituted.
  • phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties are substituted by two, three or four substituents, it is preferred that not-more than two substituents are selected from cyano and nitro. More preferably, not more than one substituent is selected from cyano and nitro.
  • phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties are substituted by two or three substituents, it is preferred that not more than one substituent is selected from -COOH, -COOR A , -COR A -S0 2 R A , -CONH2, -S0 2 NH 2 , -CONHR A , -S0 2 NHR A , -CONR A R B , -S0 2 NR A R B , -OCONH 2 , -OCONHR A , -OCONR A R B , -NHCOR A , -NR B COR A , -NHCOOR A , -NR B COOR A , -NR B COOH, -NHCOOH, -NHS0 2 R A , -NR B S0 2 R A , -NHS0 2 OR A , -NR B S0 2 OH, -NHS0 2 H, -NR B
  • phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties are unsubstituted or substituted by 1 , 2, 3 or 4 substituents, for example by 1 , 2 or 3 substituents.
  • Preferred substituents include halogen atoms and C alkyl, C 2-4 alkenyl, C alkoxy, C 2-4 alkenyloxy, C haloalkyl, C 2-4 haloalkenyl, C haloalkoxy, C 2- 4 haloalkenyloxy, hydroxyl, mercapto, cyano, nitro, CM hydroxyalkyl, C 2- 4 hydroxy alkenyl, CM
  • substituents are themselves unsubstituted. More preferred substituents include halogen atoms and unsubstituted CM alkyl, CM alkoxy, hydroxyl, CM haloalkyl, CM haloalkoxy, CM hydroxyalkyl, cyano, nitro, -SR' and -NR ' R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C 1-2 alkyl. More preferred
  • substituents include halogen atoms and Ci -2 alkyl and Ci -2 alkoxy groups.
  • salt includes base addition, acid addition and quaternary salts.
  • Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g.
  • sodium and potassium hydroxides alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
  • organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
  • Those compounds (I) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g.
  • prodrug represents a derivative of a phenylamide compound of formula (I) which is administered in a less active form and which, once administered, is prodrug is metabolised in vivo into an active metabolite of formula (I).
  • prodrug Various forms of prodrug are known in the art. For examples of such prodrugs see: Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in
  • prodrugs include cleavable esters of compounds of formula (I).
  • An in vivo cleavable ester of a compound of the invention containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically-acceptable esters for carboxy include Ci -6 alkylesters, for example methyl or ethyl esters; C 1-6 alkoxymethyl esters, for example methoxymethyl ester; C 1-6 alkanoyloxymethyl esters; phthalidyl esters; C 3-8 cycloalkoxycarbonyloxyC 1-6 alkyl esters, for example 1- cyclohexylcarbonyloxyethyl; 1 ,3-dioxolan2-ylmethyl esters, for example 5-methyl-l,3- dioxolan-2-ylmethyl; Ci -6 alkoxycarbonyloxyethyl esters, for example 1- methoxycarbonyloxy ethyl; aminocarbonylmethyl esters and mono- or di-N-(Ci -6 alkyl) versions thereof, for example N,N-dimethylaminocarbonylmethyl esters and N- ethylaminocarbonylmethyl esters; and may be formed at
  • An in vivo cleavable ester of a compound of the invention containing a hydroxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent hydroxy group.
  • Suitable pharmaceutically acceptable esters for hydroxy include C 1- alkanoyl esters, for example acetyl esters; and benzoyl esters wherein the phenyl group may be substituted with aminomethyl or -substituted mono- or di-C] ⁇ alkyl aminomethyl, for example 4- aminomethylbenzoyl esters and 4-N,N-dimethylaminomethylbenzoyl esters.
  • prodrugs include in vivo cleavable amides of a compound of formula (I).
  • examples of such in vivo cleavable amides include an N-C 1-6 alkylamide and an N,N-di-(C 1-6 alkyl)amide such as N-methyl, N-ethyl, N-propyl,
  • Preferred prodrugs of the invention include carbamate, acetyloxy and carbonate derivatives.
  • a hydroxy group of a compound of formula (I) can be present in a prodrug as -O-CONR'R", -0-COR M or -0-C(0)OR I where R I is unsubstituted or substituted C alkyl, and R 1 and R" are the same or different and represent C alkyl or NR'R" forms a 4- to 7-membered heterocyclyl ring.
  • Substituents on the alkyl and heterocyclyl groups are as defined earlier.
  • the alkyl groups in R 1 , R" and R" 1 are unsubstituted.
  • NR'R" forms a 4- to 7-membered heterocyclyl ring, preferably it is a 5- or 6-membered heterocyclyl ring.
  • the heterocyclyl ring is
  • compositions include amino acid derivatives.
  • Suitable amino acids include a-amino acids linked to group A via their -OH group.
  • Such prodrugs can cleave in vivo to produce compounds of formula (I) bearing a
  • amino acid groups are preferably employed at positions of formula (I) where a hydroxy group is eventually required.
  • exemplary prodrugs of this embodiment of the invention are therefore compounds of formula (I) bearing a group of formula -OC(0)-CH(NH 2 )R' V where R IV is an amino acid side chain.
  • Preferred amino acids include glycine, alanine, valine and serine.
  • the amino acid can also be functionalised, for example the amino group can be alkylated.
  • a suitable functionalised amino acid is N,N-dimethylglycine.
  • R 1 represents either hydrogen or hydroxy.
  • R 1 is a hydroxy group.
  • R 2 represents a hydrogen or halogen atom or a hydroxy, unsubstituted C alkyl or unsubstituted C M alkoxy group. More preferably R 2 represents a hydrogen atom.
  • R 3 represents a hydrogen or halogen atom or a hydroxy, unsubstituted * - C]- 4 alkyl or unsubstituted C alkoxy group. More preferably R 3 represents a hydroxy group.
  • R 4 represents a hydrogen or halogen atom or a hydroxy, unsubstituted C 1- alkyl or unsubstituted C M alkoxy group. More preferably R 4 represents an
  • R 5 represents a hydrogen or halogen atom or a hydroxy, unsubstituted C 1-4 alkyl or unsubstituted C 1-4 alkoxy group. More preferably R 5 represents a hydrogen atom.
  • R 6 is selected from C 1-4 alkyl and R 7 represents -CR 8 R 9 -A wherein R and R are the same or different and represent a hydrogen or halogen atom or a C alkyl, C 2- 4 alkenyl, C alkoxy, hydroxy or -NR ' R" group where R' and R " are the same or different and represent hydrogen or unsubstituted C alkyl, and A represents a phenyl ring or a 5- or 6-membered heteroaryl group and is substituted with a group W.
  • R 6 is an unsubstituted Ci -2 alkyl group, more preferably R 6 is -CH 3 .
  • R 6 is C 1-4 alkyl, preferably R 8 and R 9 , which are the same or different, represent a hydrogen or halogen atom or an unsubstituted C 1-4 alkyl or C 1-4 alkoxy Q
  • R and R which are the same or different, represent hydrogen or an unsubstituted Ci -2 alkyl. Most preferably R and R are both hydrogen.
  • R 6 is C alkyl
  • A represents a phenyl ring substituted with a group W.
  • the phenyl ring bears no substituents other than the group W.
  • R 6 represents -CH 3 and R represents -CH 2 -phenyl wherein the phenyl ring is substituted with a single group W.
  • R 6 and R 7 together with the nitrogen atom to which they are bonded, form a 5- or 6-membered heterocyclyl group which is either (a) unfused, or (b) fused to a phenyl ring or a 5- to 6- membered heteroaryl group, and wherein either the heterocyclyl group or, when fused, the heterocyclyl group or the phenyl ring or heteroaryl group to which it is fused, is substituted with a group W.
  • R 6 and R 7 together with " the nitrogen atom to which they are bonded, form a pyrrolidinyl, piperidinyl or ' isoindolinyl group which is substituted with a group W and is optionally further substituted with 1 or 2 groups which are the same or different and are selected from halogen atoms and unsubstituted C 1-4 alkyl, CM alkoxy, hydroxyl, C haloalkyl, CM haloalkoxy, CM hydroxyalkyl, cyano, nitro, -SR' and -NR ' R " groups where R ' and R " are the same or different and represent hydrogen or unsubstituted C1.2 alkyl. More preferably R 6 and R 7 , together with the nitrogen atom to which they are bonded, form a pyrrolidinyl, piperidinyl or isoindolinyl group which is substituted with a single group W.
  • Alk 1 represents a bond, an unsubstituted C alkylene group, or an unsubstituted -(Ci -2 alkylene)-NH-(Ci-4 alkylene)- group.
  • Alk 1 is an
  • unsubstituted C alkylene group it is preferably a methylene, ethylene or propylene group.
  • Alk 1 is a propylene group preferably it is a straight chain group (i.e. -CH 2 -CH 2 -C3 ⁇ 4-).
  • Alk 1 is an unsubstituted -(d. 2 alkylene)-NH-(Ci -4 alkylene)- group, preferably it is a -CH2-NH-(C 1- 4 alkylene)- group, more preferably a
  • R represents a group of formula (X) or (Y):
  • Ring D is present when group R is of formula (Y).
  • Preferred groups (Y) include those where Ring D is a non-fused 5- to 6-membered heteroaryl or heterocyclyl group where R 11 is linked to the group Alk 2 , which provides the carbon atom adjacent the nitrogen atom shown in Ring D. More preferably Ring D is a non-fused 5- to 6- membered heterocyclyl group, for example a pyrrolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,
  • Ring D is a pyrrolidinyl, piperazinyl or piperidinyl group, more preferably a piperidyl or piperazinyl group.
  • -Alk - is -C(R )-.
  • the carbon atom of Alk forms part of the ring D, and (in addition to being bonded to two other ring atoms) bears group R 12 as well as bearing group R 11 .
  • Preferred examples of R 12 are discussed in more detail below.
  • Ring D in addition to containing Alk and bearing group R , is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and C 1-4 alkyl, C 1-4 alkoxy and hydroxyl groups. More preferably Ring D, apart from containing Alk 2 and bearing group R 1 1 , is unsubstituted.
  • R 10 preferably represents a hydrogen atom or an unsubstituted C 1-2 alkyl. More preferably R 10 represents a hydrogen atom Preferably R represents a group of formula (X).
  • Alk represents a methylene group substituted with an R group and, when R represents a group of formula (X), an R 13 group.
  • R 12 and R 13 are hydrogen or the a substituents of an a-substituted or a,a-disubstituted glycine or glycine ester. These substituents may therefore be independently selected from hydrogen and the side chains of a natural or non-natural alpha-amino acid. In such side chains any functional groups may be protected.
  • amides for example as aNHCOd-C 6 alkyl amide
  • R and R include hydrogen, phenyl and groups of formula - CR a R b R c in which:
  • R a , R b and R c are the same or different and represent a hydrogen atom or a C 1-6 alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, phenyl, 5- to 6-membered heteroaryl, phenyl(C 1 - 6)alkyl or (C 3-8 )carbocyclyl group, -OH, -SH, halogen, -CN, -C0 2 H, (C 1-4 )perfluoroalkyl, -CH 2 OH, -0(Ci -6 )alkyl, -0(C 2-6 )alkenyl, -S(C 1-6 )alkyl, -SO(C 1-6 )alkyl, -S0 2 (C 1-6 ) alkyl,
  • R a , R b and R c represent a group mentioned in (a) above and the other of R a , R b and R c represents a group -Q- W wherein Q represents a bond or -0-, -S-, -SO- or -S0 2 - and W represents a phenyl, C 3-8 carbocyclyl, C 3-8 carbocyclyl(Ci -6 )alkyl, C 4-8 cycloalkenyl, C 4- 8 cycloalkenyl(C !
  • R a , R b and R c represents a group mentioned in (a) above and the other two of R a , R b and R c , together with the carbon atom to which they are attached, form a 3 to 8-membered carbocyclyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl ring, or R a , R b and R c , together with the carbon atom to which they are attached, form a tricyclic system.
  • each of R a , R b and R c is the same or different and represents a hydrogen atom or a C 1-6 alkyl, C 2-6 alkenyl, phenyl(C 1 - 6)alkyl or (C 3-8 )carbocyclyl group.
  • R c is hydrogen and R a and R b are the same or different and represent phenyl or a 5- to 6-membered heteroaryl group.
  • Particularly suitable heteroaryl groups include pyridyl.
  • R c represents a hydrogen atom or a Ci -6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, phenyl(Ci -6 )alkyl or (C 3- 8)carbocyclyl group, and R a and R b , together with the carbon atom to which they are attached, form a 3 to 8-membered carbocyclyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl ring.
  • R a , R b and R c together with the carbon atom to which they are attached, form a tricyclic system.
  • a particularly suitable tricyclic system is adamantyl.
  • R a and R b are the same or different and represent a Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or phenyl(C 1-6 )alkyl group, or a group as defined for R c below other than hydrogen, or R a and R , together with the carbon atom to which they are attached, form a C 3-8 carbocyclyl or 5- or 6-membered heterocyclyl group, and R° represents a hydrogen atom or a group selected from -OH, -SH, halogen, -CN, -C0 2 H, (C 1-4 )perfluoroalkyl, -CH 2 OH, -0(C 1-6 )alkyl, -0(C 2-6 )alkenyl, -S(C 1-6 )alkyl,
  • R c represents a group -Q-W wherein Q represents a bond or -0-, -S-, -SO- or -SO2- and W represents a phenyl, phenyl ⁇ -6)alkyl, C 3-8 carbocyclyl, C 3-8 cycIoalkyI(Ci-6)alkyl, C 4-8 cycloalkenyl, C -8 cycloalkenyl(C )-6 )alkyl, 5- or 6-membered heteroaryl or 5- or 6-membered heteroaryl(C 1-6 )alkyl group, which group W is unsubstituted or substituted by one or more substituents which are the same or different and represent hydroxyl, halogen, -CN, -CONH 2 , -CONH(C , -6 )alkyl,
  • R is a group of formula (X)
  • the substituents R and R taken together with the carbon to which they are attached, form a 3- to 6- membered saturated carbocyclyl or heterocyclyl ring.
  • Suitable carbocyclyl rings include cyclopropyl, cyclopentyl and cyclohexyl ring;
  • suitable heterocyclyl rings include piperidin-4-yl rings.
  • R and R are the same or different and represent hydrogen, C 1-6 alkyl, C 3-7 carbocyclyl, Cg-io aryl, -(CM alkyl)-(C 0- io aryl), or -(C alkyl)-(C 3-7 carbocyclyl); or
  • alkyl groups and moieties are unsubstituted or substituted with 1 or.2 substituents selected from unsubstituted C alkyl, C alkoxy, hydroxy and -NR'R" groups where R' and R" are the same or different and represent hydrogen or unsubstituted C 1-2 alkyl, and wherein the aryl and carbocyclyl groups and moieties are unsubstituted or substituted with 1 or 2 substituents selected from halogen atoms and unsubstituted C 1-4 alkyl, C alkoxy, hydroxyl, CM haloalkyl, CM haloalkoxy, C ]-4 hydroxyalkyl, cyano, nitro, -SR' and -NR'R" groups where R ' and R " are the same or different and represent hydrogen or unsubstituted Ci -2 alkyl.
  • R 12 and R 13 do not together form a carbocyclyl group, then preferably R 12 and R 13 are the same or different and represent a hydrogen atom or an unsubstituted group selected from C 1-4 alkyl, C 3-7 carbocyclyl, phenyl, -hydroxy-(Ci.4)alkyl,
  • R 12 and R 13 do not together form a carbocyclyl group, then preferably one of R and R is other than hydrogen. Where one of R and R is methyl, then preferably the other group is hydrogen or methyl.
  • R 12 and R 13 do not together form a carbocyclyl group, then preferably one of R 12 and R 13 is hydrogen or unsubstituted C 1-2 alkyl and the other of R 12 and R 13 is an unsubstituted group selected from C 1-4 alkyl, C 3 . 7 carbocyclyl, phenyl,
  • R 12 and R 13 form a carbocyclyl group, together with the carbon atom to which they are bonded, preferably the carbocyclyl group is an unsubstituted C 3-7 carbocyclyl group.
  • a more preferred carbocyclyl group is a cyclopentyl group.
  • R 11 is either a carboxylic acid group -COOH or an ester group -COOR 20 .
  • ester or "esterified carboxyl group” in connection with substituent R 11 above means a group -COOR 20 in which R 20 is the group characterising the ester, notionally derived from the alcohol R 20 -OH.
  • R 11 is preferably an ester group -COOR 20 .
  • R 11 is an ester group, it must be one which in the compound of the invention is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group.
  • Intracellular carboxylesterase enzymes capable of hydrolysing the ester group of a compound of the invention to the corresponding acid include the three known human enzyme isotypes hCE-1, hCE-2 and hCE-3. Although these are considered to be the main enzymes other enzymes such as biphenylhydrolase (BPH) may also have a role in hydrolysing the conjugates.
  • BPH biphenylhydrolase
  • the carboxylesterase hydrolyses the free amino acid ester to the parent acid it will also hydrolyse the ester motif when covalently conjugated to the HSP90 inhibitor.
  • the broken cell assay described later provides a straightforward, quick and simple first screen for esters which have the required hydrolysis profile. Ester motifs selected in that way may then be re-assayed in the same carboxylesterase assay when conjugated to the HSP90 inhibitor via the chosen conjugation chemistry, to confirm that it is still a carboxylesterase substrate in that background.
  • Macrophages are known to play a key role in inflammatory disorders through the release of cytokines in particular TNF-a and IL-1. In rheumatoid arthritis they are major contributors to the maintenance of joint inflammation and joint destruction.
  • Macrophages are also involved in tumour growth and development. Hence agents that selectively target macrophage cell proliferation could be of value in the treatment of cancer and autoimmune disease. Targeting specific cell types would be expected to lead to reduced side-effects.
  • the inventors have discovered a method of targeting HSP90 inhibitors to macrophages and other cells derived from the myelo-monocytic lineage such as monocytes, osteoclasts and dendritic cells. This is based on the observation that the way in which the esterase motif is linked to the HSP90 inhibitor determines whether it is hydrolysed, and hence whether or not it accumulates in different cell types.
  • macrophages and other cells derived from the myelo- monocytic lineage contain the human carboxylesterase hCE-1 whereas other cell types do not.
  • macrophage or macrophages will be used to denote macrophages (including tumour associated macrophages) and/or monocytes.
  • esters groups -COOR 20 include those wherein R 20 is -CR 14 R 15 R 16 wherein:
  • R 15 represents hydrogen or a group of formula -[C
  • R 17 is hydrogen or C 1-4 alkyl
  • R 16 represents hydrogen or C alkyl
  • R 14 represents hydrogen or CM alkyl
  • R 15 represents a phenyl or a 5- or 6-membered heteroaryl group optionally fused to a further phenyl, 5- or 6-membered heteroaryl, C 3- 7 carbocyclyl or 5- or 6-membered heterocyclyl group
  • R 16 represents hydrogen or C alkyl
  • R 14 represents hydrogen
  • R 15 represents a group of formula -(Alk 4 )-NR 18 R 19 wherein Alk 4
  • R 18 and R 19 are the same or different and represent hydrogen or C 1-4 alkyl, or (b) R 18 and R 19 , together with the nitrogen atom to which they are bonded, form a 5- or 6- membered heteroaryl or 5- or 6-membered heterocyclyl group optionally fused to a further phenyl, 5- or 6-membered heteroaryl, C 3-7 carbocyclyl or 5- or 6-membered heterocyclyl group;
  • R 16 represents hydrogen or C alkyl, and R 14 represents hydrogen; or
  • R 15 and R 16 together with the carbon atom to which they are bonded, form a phenyl, 5- or 6-membered heteroaryl, C 3-7 carbocyclyl or 5- or 6- membered heterocyclyl group which is optionally fused to a further phenyl, 5- or 6-membered heteroaryl, C 3-7 carbocyclyl or 5- or 6- membered heterocyclyl group, and R 14 represents hydrogen.
  • Preferred substituents on the alkyl, alkylene and alkenyl groups in R 14 , R 15 , R 16 , R 17 , R 18 , R l9 and Alk 4 groups include one or two substituents which are the same or different and are selected from halogen, CM alkyl, C 2 ⁇ alkenyl, C 1-4 alkoxy, hydroxyl and -NR ' R" wherein R' and R" are the same or different and represent hydrogen or Ci -2 alkyl. More preferred substituents are halogen, C 1-2 alkoxy, hydroxyl and -NR ' R" wherein R' and R" are the same or different and represent hydrogen or C 1-2 alkyl. Most preferably the alkyl, alkylene and alkenyl groups in R 15 , R 16 and Alk 4 are unsubstituted.
  • Preferred substituents on the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R 15 , R 16 , R 18 and R 19 groups include one or two substituents which are the same or different and are selected from halogen atoms and C alkyl, CM alkylene, C 1-4 alkoxy, CM haloalkyl, hydroxyl, cyano, nitro and -NR ' R" groups wherein each R' and R" is the same or different and represents hydrogen or C 1-4 alkyl, more preferably halogen atoms and C 1-2 alkyl, C 1-2 alkylene, Ci -2 alkoxy and hydroxyl groups.
  • the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R 15 , R 16 , R 18 and R 19 are unsubstituted or substituted by a C 1-2 alkylene group, in particular a methylene group.
  • the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in or formed by R 15 , R 16 , R 18 and R 19 are unsubstituted.
  • R 15 represents a group of formula -[CM alkyleneJ b -iZ' tC alkyl], preferably either a or b is zero, for example both a and b are zero.
  • [C 1-4 alkylene] is present, it is preferably a Ci -3 alkylene, more preferably a C 1-2 alkylene such as a group -CH 2 -CH 2 -.
  • R 15 represents a group of formula -[C alkylene]b-(Z I ) a -[Ci-4 alkyl], preferably C 1-4 alkyl is a C 1-3 alkyl group such as methyl, ethyl or n-propyl, most preferably meth l .
  • Z 1 is preferably -O- or -NR 17 - wherein R 17 is hydrogen or C 1-2 alkyl, more preferably Z 1 is -0-.
  • R 15 represents a group of formula -[CM alkylene] b -(Z 1 ) a -[C 2 . 4 alkenyl], preferably either a or b is zero, more preferably both a and b are zero.
  • [C alkylene] is present, it is preferably a C 1-3 alkylene, more preferably a C 1-2 alkylene.
  • Z 1 is preferably -O- or -NR 17 - wherein R 17 is hydrogen or Ci -2 alkyl, more preferably Z 1 is -0-. Most preferably Z 1 is absent (i.e. a is zero).
  • R 15 represents hydrogen or a group of formula -[CM alkylene] (,-( ⁇ ') 3 -[ ⁇ ⁇ alkyl] or -[C 1-4 alkylene] b -(Z 1 ) a -[C 2- 4 alkenyl]
  • R 15 represents hydrogen or a group of formula -[CM alkylene] b -(Z') a -[CM alkyl] or -[CM alkylene] b -(Z 1 ) a -[C 2-4 alkenyl]
  • R 16 represents hydrogen or Ci-2 alkyl, more preferably hydrogen or methyl.
  • R 15 represents hydrogen or a group of formula -[CM alkylene] b-(Z l ) a - [CM alkyl] or -[C 1-4 alkylene] b -(Z 1 ) a -[C 2-4 alkenyl], preferably R 14 represents hydrogen or C 1-2 alkyl, more preferably R 14 represents hydrogen or methyl.
  • R 15 represents hydrogen or a group of formula -[C
  • alkylene]b-(Z 1 ) A -[C alkyl] or -[C 1-4 alkenyl], preferably the alkyl, alkylene and alkenyl groups in both R 15 and R 16 are unsubstituted.
  • R 15 represents a phenyl or a 5- or 6-membered heteroaryl group optionally fused to a further phenyl, 5- or 6-membered heteroaryl, C 3-7 carbocyclyl or 5- or 6- membered heterocyclyl group, preferably it represents a non-fused phenyl or a non- fused 5- to 6-membered heteroaryl group.
  • Preferred heteroaryl groups include pyridyl, pyrrolyl, isothiazolyl, pyrazolyl and isoxazolyl, most preferably pyridyl.
  • R 15 represents a phenyl or a 5- or 6-membered heteroaryl group optionally fused to a further phenyl, 5- or 6-membered heteroaryl, C 3-7 carbocyclyl or 5- or 6- membered heterocyclyl group, preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in R 13 are unsubstituted .
  • R 15 represents a phenyl or a 5- or 6-membered heteroaryl group optionally fused to a further phenyl, 5- or 6-membered heteroaryl, C 3-7 carbocyclyl or 5- or 6- membered heterocyclyl group
  • R 16 preferably represents hydrogen or C alkyl, more preferably hydrogen or Ci -2 alkyl, most preferably hydrogen.
  • the C alkyl groups of R 16 are unsubstituted.
  • Alk 4 preferably represents a C 1-2 alkylene group, preferably either -CH 2 - or -CH 2 CH 2 -.
  • R 1 S represents a group of formula -(Alk 4 )-NR 18
  • R 19 and R 18 and R 19 are the same or different and represent hydrogen or C 1-4 alkyl, preferably R represents hydrogen or Ci_ 2 alkyl, more preferably R 18 represents a methyl group.
  • R 15 represents a group of formula -(Alk )-NR ,8 R 19 and R 18 and R 19 are the same or different and represent hydrogen or C alkyl, preferably R 19 represents hydrogen or C 1-2 alkyl, more preferably R 19 represents a methyl group.
  • R 15 represents a group of formula -(Alk 4 )-NR I8 R 19 and R 18 and R 19 , together with the nitrogen atom to which they are bonded, form a 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl group optionally fused to a further phenyl, 5- or 6-membered heteroaryl, C 3-7 carbocyclyl or 5- or 6-membered heterocyclyl group, preferably they form a non-fused 5- to 6-membered heteroaryl or non-fused 5- to 6- membered heterocyclyl group. More preferably they form a 5- to 6-membered heterocyclyl group.
  • Preferred heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl, most preferably morpholinyl.
  • Alk 4 preferably represents a Ci -2 alkylene group, more preferably a group -C3 ⁇ 4CH 2 -.
  • R 16 preferably represents hydrogen or C 1-2 alkyl, most preferably hydrogen.
  • R 15 represents a group of formula -(Alk 4 )-NR 18 R 19
  • R 18 and R 19 are unsubstituted.
  • R 15 represents a group of formula -(Alk 4 )-NR 18 R 19
  • preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups in R 18 and R 19 are unsubstituted.
  • R 15 represents a group of formula -(Alk 4 )-NR 18 R 19
  • preferred groups include -CH 2 -CH 2 -NMe 2 and -CH 2 -CH 2 -morpholinyl.
  • R 15 and R 16 together with the carbon atom to which they are bonded, form a phenyl, 5- or 6-membered heteroaryl, C 3-7 carbocyclyl or 5- or 6-membered heterocyclyl group which is optionally fused to a further phenyl, 5- or 6-membered heteroaryl, C 3-7 carbocyclyl or 5- or 6-membered heterocyclyl group
  • preferred groups include non-fused phenyl, non-fused 5- to 6-membered heteroaryl, non-fused 5- to 6- membered heterocyclyl, non-fused C 3-7 carbocyclyl and C 3-7 carbocyclyl fused to a phenyl ring, more preferably non-fused phenyl, non-fused 5- to 6-membered
  • heterocyclyl non-fused C 3-7 carbocyclyl and C 3-7 carbocyclyl fused to a phenyl ring.
  • preferred non-fused 5- to 6-membered heterocyclyl groups include piperidinyl, tetrahydrofuranyl, piperazinyl, morpholinyl and pyrrolidinyl groups, more preferably piperidinyl and tetrahydrofuranyl groups.
  • preferred non-fused C 3-7 carbocyclyl groups include cyclopentyl and cyclohexyl, more preferably cyclopentyl.
  • preferred C 3-7 carbocyclyl groups fused to a phenyl ring include indanyl.
  • R 15 and R 16 form a cyclic group together with the carbon atom to which they are bonded, preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups formed are unsubstituted or substituted by one or two substituents which are the same or different and are selected from halogen atoms and C alkyl, C alkylene, C alkoxy, C haloalkyl, hydroxyl, cyano, nitro and -NR'R" groups wherein each R' and R" is the same or different and represents hydrogen or C alkyl, more preferably selected from halogen atoms or Ci -2 alkyl, C 1-2 alkylene, C 1-2 alkoxy and hydroxyl groups.
  • the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups formed are unsubstituted or substituted by a Ci -2 alkyl group (such as a methyl group) or by a Ci -2 alkylene group (such as by a methylene group). Even more preferably the phenyl, heteroaryl, carbocyclyl and heterocyclyl groups so formed are unsubstituted.
  • R 11 groups are -COOH and -COOR 20 where R 20 represents C 1-4 alkyl groups (such as methyl, ethyl, n- or iso-propyl and n-, sec- and tert-butyl), C 3- 7 carbocyclyl groups (such as cyclopentyl and cyclohexyl), C 2 ⁇ t alkenyl groups (such as allyl), and also phenyl, benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl, methoxyethyl, indanyl, norbonyl, dimethylaminoethyl and morpholinoethyl groups.
  • R 20 represents C 1-4 alkyl groups (such as methyl, ethyl, n- or iso-propyl and n-, sec- and tert-butyl
  • R represents C alkyl or C 3-7 carbocyclyl.
  • R 1 1 is -COOR 20 more preferably R 20 represents unsubstituted C 1-4 alkyl or C 3-7 carbocyclyl.
  • Most preferred R groups include cyclopentyl, t-butyl and iso-propyl.
  • a compound which is (a) a phenylamide derivative of formula (IA) or a tautomer thereof, or (b) a pharmaceutically acceptable salt, N-oxide, hydrate, prodrug or solvate thereof:
  • R 4 represents an unsubstituted C 1- alkyl group; either:
  • R 6 represents -CH 3
  • R 7 represents -CR 8 R 9 -A wherein R 8 and R 9 are the same or different and represent a hydrogen or halogen atom or an unsubstituted C alkyl or C alkoxy group, and A represents a phenyl ring substituted with a group W; or
  • o R and R together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine or isoindoline group which is substituted with a group W and which is optionally further substituted with 1 or 2 groups which are the same or different and are selected from halogen atoms and unsubstituted C alkyl, C alkoxy, hydroxyl, CM haloalkyl, C haloalkoxy, CM hydroxyalkyl, cyano, nitro, -SR ' and -NR'R" groups where R' and R " are the same or different and represent hydrogen or unsubstituted C 1-2 alkyl;
  • Alk 1 represents a bond, an unsubstituted C alkylene group, or an unsubstituted -(Ci -2 alkylene)-NH-(C M alkylene)- group;
  • R represents a group of formula (X) wherein R 10 represents hydrogen
  • Alk represents a group of formula -C(R )(R )- wherein either:
  • R'" and R ,J are the same or different and represent hydrogen, Cj -6 alkyl, C 3-7 carbocyclyl, Ce-io aryl, -(C ]-4 alkyl)-(C6-io aryl), or -(CM alkyl)-(C 3-7 carbocyclyl); or
  • alkyl groups and moieties in R 12 and R 13 are unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted CM alkyl, CM alkoxy, hydroxy and -NR ' R" groups where R ' and R" are the same or different and represent hydrogen or unsubstituted C 1-2 alkyl, and wherein the aryl and carbocyclyl groups and moieties in R 12 and R 13 are unsubstituted or substituted with 1 or 2 substituents selected from halogen atoms and unsubstituted CM alkyl, CM alkoxy, hydroxyl, CM haloalkyl, C haloalkoxy, CM hydroxyalkyl, cyano, nitro, -SR' and
  • R' and R" are the same or different and represent hydrogen or unsubstituted C 1-2 alkyl; and R 11 is selected from -COOH and -COOR 20 wherein R 20 represents unsubstituted C alkyl or C 3-7 carbocyclyl.
  • R 4 represents isopropyl. Furthermore, preferably either:
  • R represents -CH 3
  • R represents -CH 2 -phenyl wherein the phenyl ring is substituted with a single group W;
  • R 6 and R 7 together with the nitrogen atom to which they are bonded. form a pyrrolidinyl, piperidinyl or isoindolinyl group which is substituted with a single group W.
  • R 12 and R 13 are hydrogen or unsubstituted C 1-2 alkyl and the other of R 12 and R 13 is an unsubstituted group selected from C alkyl, C 3-7 carbocyclyl, phenyl, -hydroxy-(Ci )alkyl, -(C 1-4 )alkoxy-(Ci-4)alkyl, -(d ⁇ alkyl-phenyl or -(C 1-2 )alkyl-(C 3-7 )carbocyclyl.
  • Particularly preferred compounds of formula (I) are:
  • cyclopentyl 1 [(3 - ⁇ [ ⁇ [2,4-dihydroxy- 5 -(propan-2 - yl)phenyl]carbonyl ⁇ (methyl)amino]methyl ⁇ benzyl)amino]cyclopentanecarboxylate; cyclopentyl (25)-[(3- ⁇ [ ⁇ [2,4-dihydroxy-5-(propan-2- yl)phenyl]carbonyl ⁇ (methyl)amino]methyl ⁇ benzyl)amino](phenyl)ethanoate;
  • the compounds with which the invention is concerned are inhibitors of HSP90 activity and are therefore of use for treatment of cancer, autoimmune and inflammatory diseases, including chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, diabetes, atopic dermatitis, graft versus host disease, systemic lupus erythematosis, viral infection, Alzheimer's disease and others.
  • autoimmune and inflammatory diseases including chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, diabetes, atopic dermatitis, graft versus host disease, systemic lupus erythematosis, viral infection, Alzheimer's disease and others.
  • the compounds may be used in the treatment of cancer, autoimmune and inflammatory diseases, including chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, atopic dermatitis, graft versus host disease, systemic lupus erythematosis, viral infection and Alzheimer's disease.
  • a preferred utility of the compounds of the invention is for use in the treatment of cancer, in particular breast cancer, ovarian cancer, pancreatic cancer or hepatocellular carcinoma.
  • Another preferred utility of the compounds of the invention is for use in the treatment of inflammation.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial, but an exemplary dosage would be 0.1 -lOOOmg per day.
  • the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
  • the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl- pyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil
  • oily esters such as glycerine, propylene
  • the drug may be made up into a cream, lotion or ointment.
  • Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
  • the drug may be formulated for aerosol delivery for example, by pressure-driven jet atomizers or ultrasonic atomizers, or preferably by propellant-driven metered aerosols or propellant-free administration of micronized powders, for example, inhalation capsules or other "dry powder" delivery systems.
  • Excipients such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavourings, and fillers (e.g. lactose in the case of powder inhalers) may be present in such inhaled formulations.
  • Nebulator®, Volumatic®), and automatic devices emitting a puffer spray for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhalers for example as described in European Patent Application EP 0 505 321).
  • the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle.
  • Additives for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
  • the active ingredient may also be administered parenterally in a sterile medium.
  • the drug can either be suspended or dissolved in the vehicle.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the compounds of the invention may be used in conjunction with a number of known pharmaceutically active substances.
  • the compounds of the invention may be used with cytotoxics, HDAC inhibitors, kinase inhibitors,
  • cytotoxics include, for example, taxanes, platins, anti-metabolites such as 5-fluoracil, topoisomerase inhibitors and the like.
  • the medicaments of the invention comprising amino acid derivatives of formula (I), tautomers thereof or pharmaceutically acceptable salts, N-oxides, hydrates, prodrugs or solvates thereof therefore typically further comprise a cytotoxic, an HDAC inhibitor, a kinase inhibitor, an aminopeptidase inhibitor and/or a monoclonal antibody.
  • composition comprising:
  • aminopeptidase inhibitor and/or a monoclonal antibody and/or a monoclonal antibody; and (c) a pharmaceutically acceptable carrier or diluent.
  • a product comprising: (a) phenylamide derivative of formula (I), a tautomer thereof or a pharmaceutically acceptable salt, N-oxide, hydrate, prodrug or solvate thereof; and
  • aminopeptidase inhibitor and/or a monoclonal antibody for the separate, simultaneous or sequential use in the treatment of the human or animal body.
  • the compounds of the invention may be prepared by a number of processes generally described below and more specifically in the Examples hereinafter. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxyl, amino and carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions [see for example Greene, T.W.,
  • the amino acid ester building blocks can be prepared in a number of ways.
  • Scheme 1 illustrates the main routes employed for their preparation for the purpose of this application. To the chemist skilled in the art it will be apparent that there are other methodologies that will also achieve the preparation of these intermediates. Examples of the preparation of such intermediates are described in WO2009/106848,
  • the isoindoline based Hsp90 inhibitors can be prepared in a number of ways.
  • Scheme 2 illustrates the main routes employed for their preparation for the purpose of this application.
  • Scheme 3 Generic scheme for the preparation of piperidine based inhibitors of Hsp90 (R 12 , R 13 and R 20 are as defined herein, P is a suitable protecting group)
  • Hsp90 (R , R' J and are as defined herein, P is a suitable protecting group):
  • Hsp90 (R , R ,J and R iU are as defined herein, P is a suitable protecting group):
  • the pyrrolidine based Hsp90 inhibitors can be prepared in a number of ways.
  • Scheme 6 illustrates the main routes employed for their preparation for the purpose of this application. To the chemist skilled in the art it will be apparent that there are other methodologies that will also achieve the preparation of these intermediates
  • Boc tert-butoxycarbonyl
  • DCM dichloromethane
  • Dess-Martin periodinane 1,1,1 -Triacetoxy- 1 , 1 -dihydro- 1 ,2-benziodoxol-3( 1 H)-one
  • DIPEA diisopropylethylaraine
  • EDCI N-CS-Dimethylaminopropy ⁇ -N'-ethylcarbodiimide hydrochloride
  • HATU 2-(lH-7-Azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium
  • HOBt 1 -hydroxybenzotriazole
  • LiAlLL; lithium aluminium hydride
  • MgS0 4 magnesium sulfate
  • NaHC0 3 sodium hydrogen carbonate
  • UV spectra were recorded at 220 and 254 nm using a G1315B DAD detector.
  • Mass spectra were obtained over the range m/z 150 to 800 on a LC/MSD SL G1956B detector. Data were integrated and reported using ChemStation and ChemStation Data
  • the solid obtained in Stage 1 was broken into small chunks, and dissolved in toluene (500 mL). The solution was cooled (ice bath), then trifluoromethanesulfonic acid (52 mL, 588 mmol) was added slowly via a dropping funnel. After addition was complete the mixture was stirred for 30 minutes, warmed to room temperature and stirred for a further 2 hours. Acetyl chloride (4 ml, 56 mmol) was added and the solution stirred for a further 18 hours. The mixture was then poured into a 3 litre separating funnel and quenched by addition of sodium acetate solution (48.00 g in 400 mL water).
  • stage 1 To the product obtained in stage 1 (3.540 g, 10.0 mmol) in dioxane (20 mL) was added HC1 (20 mL, 4M solution in dioxane, 80 mmol). The solution was stirred at room temperature for 1 hour then concentrated under vacuum to yield the desired product (3.270 g, 100% yield, dihydrochloride salt) which was used without further purification.
  • LC/MS m/z 255.25 [M+H] +
  • the aqueous layer was then basified by addition of sodium hydroxide and di-tert-butyl dicarbonate (9.0 g, 27 mmol) was added. The mixture was stirred at room temperature for 3 hours, then product was extracted with ethyl acetate (3 times 250 mL), the combined organic extracts were dried (MgS0 4 ) and concentrated. To the residue obtained (1.278 g, 16% yield) was added HCl (10 mL, 4M solution in dioxane). The solution was stirred at room temperature for 1 hour, then concentrated under vacuum. The solid obtained was washed with diethyl ether (2 times 50 mL), and dried to yield the desired product (0.890 g, 23% yield).
  • Example 11 Step 1 To a solution of Intermediate J (0.150 g, 0.3 mmol) in dichloroethane (10 mL) was added (S)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester (0.069 g, 0.3 mmol) and sodium triacetoxyborohydride (0.127 g, 0.6 mmol). The solution was stirred at room temperature for 2 hours. An aqueous solution of sodium hydrogen bicarbonate (10 mL) was added and the desired product extracted into ethyl acetate (3 times 10 mL). The organic layers were combined, dried (MgS0 4 ) and concentrated.
  • Example 24 - /erf-butyl N-[(l- ⁇ [2,4-dihydroxy-5-(propan-2- yI)phenyl]carbonyl ⁇ piperidin-4-yl)methyl]-L-leucinate Prepared from Intermediate C and L-leucine tert-butyl ester.
  • Stage 2 2,4-bis(benzyloxy)-A'-[4-(2-hydroxyethyl)benzyl]-N-methyI-5-(prop-l-en- 2-yl)benzamide
  • N,N-diisopropylethylamine 5 mL, 28.7 mmol
  • Intermediate A 1.01 g, 2.7 mmol
  • HATU 1.08 g, 2.84 mmol
  • Example 75 was prepared in a simiar fashion to Example 74 starting with (S)-l- pyrrolidin-2-yl-methanol and Intermediate A.
  • Example 80 N-[3-(2- ⁇ [2,4-dihydroxy-5-(propan-2-yl)phenyl]carbonyl ⁇ -2,3- dihydro-lH-isoindol-5-yI)propyl]-L-leucine
  • Example 110 3-cyclohexyl-/V-(l- ⁇ [2,4-dihydroxy-5-(propan-2- yl)pheny 1] carbonyl ⁇ piperidin-4-y l)-L-alanine Method D - Prepared from Example 13

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Abstract

L'invention concerne un composé qui est (a) un dérivé de phénylamide de formule (I) ou un tautomère de celui-ci ou (b) un sel pharmaceutiquement acceptable, un N-oxyde, un hydrate, un précurseur de médicament ou un solvate de celui-ci : R1, R2, R3, R4, R5, R6 et R7 étant tels que définis dans le présent document. Les composés sont utiles dans le traitement de maladies médiées par HSP90.
PCT/GB2011/000879 2010-06-11 2011-06-10 Dérivés de benzamide et leur utilisation comme inhibiteurs de hsp90 WO2011154708A1 (fr)

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BR112012031634A BR112012031634A2 (pt) 2010-06-11 2011-06-10 composto, composição farmacêutica, uso de um composto, e método para tratar um paciente que sofre de ou susceptível a um distúrbio
NZ605558A NZ605558A (en) 2010-06-11 2011-06-10 Benzamide derivatives and their use as hsp90 inhibitors
SG2012090304A SG186232A1 (en) 2010-06-11 2011-06-10 Benzamide derivatives and their use as hsp90 inhibitors
CA2802279A CA2802279A1 (fr) 2010-06-11 2011-06-10 Derives de benzamide et leur utilisation comme inhibiteurs de hsp90
ES11726470.5T ES2587256T3 (es) 2010-06-11 2011-06-10 Derivados de la benzamida y su uso como inhibidores de HSP90
DK11726470.5T DK2580193T3 (en) 2010-06-11 2011-06-10 Benzamide AND USE THEREOF AS HSP90 INHIBTORER
JP2013513747A JP5955317B2 (ja) 2010-06-11 2011-06-10 Ｈｓｐ９０阻害剤としてのベンズアミド誘導体およびその使用
CN201180038937.2A CN103068799B (zh) 2010-06-11 2011-06-10 作为hsp90抑制剂的苯甲酰胺衍生物及其应用
KR1020137000721A KR20130112026A (ko) 2010-06-11 2011-06-10 벤즈아미드 유도체 및 hsp90 억제제로서의 이의 용도
EP11726470.5A EP2580193B1 (fr) 2010-06-11 2011-06-10 Dérivés de la benzamide et leur utilisation comme inhibiteurs de la hsp90
US13/703,387 US9321718B2 (en) 2010-06-11 2011-06-10 Benzamide derivatives and their use as HSP90 inhibtors
EA201270816A EA021237B1 (ru) 2010-06-11 2011-06-10 Производные бензамида и их применение в качестве ингибиторов hsp90
MX2012014506A MX341341B (es) 2010-06-11 2011-06-10 Derivados de benzamida y su uso como inhibidores de proteina de choque termico 90 kda (hsp90).
AU2011263543A AU2011263543B2 (en) 2010-06-11 2011-06-10 Benzamide derivatives and their use as HSP90 inhibtors
IL223514A IL223514A (en) 2010-06-11 2012-12-09 The history of benzamide and its use as 90hsp inhibitors
ZA2013/00036A ZA201300036B (en) 2010-06-11 2013-01-02 Banzamide derivatives and their use as hsp90 inhibitors
US15/073,352 US20160193200A1 (en) 2010-06-11 2016-03-17 Benzamide derivatives and their use as hsp90 inhibtors

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US15/073,352 Continuation US20160193200A1 (en) 2010-06-11 2016-03-17 Benzamide derivatives and their use as hsp90 inhibtors

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WO2017131500A1 (fr) * 2016-01-29 2017-08-03 계명대학교 산학협력단 Nouveau composé ayant une activité inhibitrice de hsp90 ou sel pharmaceutiquement acceptable de celui-ci, et utilisation médicale de celui-ci
WO2019027203A1 (fr) * 2017-08-02 2019-02-07 계명대학교 산학협력단 Stéréoisomère à base de dihydroxyphényle ayant une activité d'inhibition de hsp90 et son utilisation médicale

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GB201713975D0 (en) 2017-08-31 2017-10-18 Macrophage Pharma Ltd Medical use
CA3125350A1 (fr) 2018-12-31 2020-07-09 Biomea Fusion, Llc Inhibiteurs irreversibles de l'interaction menine-mll
TW202043205A (zh) 2018-12-31 2020-12-01 美商拜歐米富士恩有限公司 Menin-mll相互作用之抑制劑
IL310717A (en) 2021-08-20 2024-04-01 Biomea Fusion Inc Crystalline form of N-[4-[4-(4-morpholinyl)-7H-PYRROLO[2,3-D]PYRIMIDIN-6-YL]PHENYL]-4-[[3(R)-[(1-OXO ] -2-PROPEN-1-YL)AMINO]-1-PIPERIDINYL]METHYL]-2-PYRIDINECARBOXAMIDE, IRREVERSIBLE MENIN-MLL INHIBITOR FOR CANCER TREATMENT

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Cited By (8)

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Publication number Priority date Publication date Assignee Title
CN102924318A (zh) * 2012-11-26 2013-02-13 武汉大学 阻断h5n1禽流感病毒进入的l-亮氨酸衍生物及其制备方法
CN102924318B (zh) * 2012-11-26 2014-06-04 武汉大学 阻断h5n1禽流感病毒进入的l-亮氨酸衍生物及其制备方法
WO2017131500A1 (fr) * 2016-01-29 2017-08-03 계명대학교 산학협력단 Nouveau composé ayant une activité inhibitrice de hsp90 ou sel pharmaceutiquement acceptable de celui-ci, et utilisation médicale de celui-ci
CN108884021A (zh) * 2016-01-29 2018-11-23 启明大学校产学协力团 具有hsp90抑制活性的新型化合物或其药学上可接受的盐及其医疗用途
US10464907B2 (en) 2016-01-29 2019-11-05 Industry Academic Cooperation Foundation Keimyung University Compound having HSP90 inhibitory activity or pharmaceutically acceptable salt thereof, and medical use thereof
US10889552B2 (en) 2016-01-29 2021-01-12 Oncozen Co.. Ltd. Dihydroxybenzamide compound having HSP90 inhibitory activity or pharmaceutically acceptable salt thereof, and medical use thereof
CN108884021B (zh) * 2016-01-29 2021-06-01 恩科森株式会社 具有hsp90抑制活性的新型化合物或其药学上可接受的盐及其医疗用途
WO2019027203A1 (fr) * 2017-08-02 2019-02-07 계명대학교 산학협력단 Stéréoisomère à base de dihydroxyphényle ayant une activité d'inhibition de hsp90 et son utilisation médicale

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US9321718B2 (en) 2016-04-26
EA021237B1 (ru) 2015-05-29
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AU2011263543B2 (en) 2014-10-02
BR112012031634A2 (pt) 2016-11-08
US20130143926A1 (en) 2013-06-06
AU2011263543A1 (en) 2013-01-10
CA2802279A1 (fr) 2011-12-15
SG186232A1 (en) 2013-01-30
JP5955317B2 (ja) 2016-07-20
ZA201300036B (en) 2013-09-25
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